Cardiovascular Risks with Testosterone

Special guest Steven E. Nissen, MD, MACC, the Chief Academic Officer at the Heart and Vascular Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine and a Professor of Medicine at the Cleveland Clinic Lerner School of Medicine at Case Western Reserve University joins us to talk about cardiovascular risks with testosterone.

Listen in as they discuss the latest evidence regarding cardiovascular risks with testosterone replacement therapy in men with hypogonadism.

You’ll also hear practical advice from panelists on TRC’s Editorial Advisory Board:

• Douglas S. Paauw, MD, MACP, Professor of Medicine at the University of Washington School of Medicine
• Craig D. Williams, PharmD, FNLA, BCPS, Clinical Professor of Pharmacy Practice at the Oregon Health and Science University

For the purposes of disclosure, Dr. Steven Nissen reports relevant financial relationships [cardiology] with AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharma, Novartis, Pfizer, Silence Therapeutics (grants/research support). The other speakers have nothing to disclose. All relevant financial relationships have been mitigated.

TRC Healthcare offers CE credit for this podcast. Log in to your Pharmacist’s Letter or Prescriber's Letter account and look for the title of this podcast in the list of available CE courses.

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The clinical resources mentioned during the podcast are part of a subscription to Pharmacist’s Letter and Prescriber's Letter: 

• [Chart]: Comparison of Testosterone Products

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Transcript

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Narrator 0:06

Welcome to Medication Talk, the official podcast of TRC Healthcare, Homopharmacist Letter, Prescriber's Letter, RX Advanced, and the most trusted clinical resources. On today's episode, listen in as our expert panel discusses the latest evidence regarding cardiovascular risks with testosterone replacement therapy in men with hypogonadism. Our guest today is Dr. Stephen Ninson from the Cleveland Clinic. You'll also hear practical advice from other panelists on TRC's editorial advisory board, Dr. Douglas Powell from the University of Washington School of Medicine, and Dr. Craig Williams from the Oregon Health and Science University. This podcast is an extract from TRC's Emerging Recommendations panel webinar. Each month, experts and frontline providers discuss current medication therapy topics and practical recommendations to include in TRC's letter articles. The full webinar originally aired on July 24th, 2023.

CE Narrator 1:00

And now the CE information.

Narrator 1:04

This podcast offers continuing education credit for pharmacists, physicians, and nurses. Please log into your pharmacist letter or prescriber's letter account and look for the title of this podcast in the list of available CE courses. For the purposes of disclosure, Dr. Steven Nissan reports a relevant financial relationship by receiving grants or research support from Affy, Amgen, AstraZeneca, Bristol Meyer Squibb, Eli Lilly, Esperion, Medtronic, Myocardia, New Amsterdam Pharma, Novartis, Pfizer, and Silence Therapeutics. The other speakers you'll hear have nothing to disclose. All relevant financial relationships have been mitigated. Now, let's join TRC editor, Dr. Sarah Clockers, and start our discussion.

Sara Klockars 1:51

We're talking about this now because new evidence will help clarify cardiovascular risk of testosterone replacement in men with hypogonadism. And so to kick off our discussion, Steve, can you give us some background as to why we have the phase four traverse trial looking at the cardiovascular safety of testosterone?

Steven E. Nissen 2:14

I would be pleased to. First of all, this goes back a long way. It goes back to 2010. The NIH sponsored a trial, a small trial, which was looking at the testosterone replacement therapy. And it was stopped by the data monitoring committee because of an excess in cardiovascular events. Stopped early. And that information went to the FDA and it did raise some alarm bells. Now there's been concerns about testosterone safety. So eventually in 2015, uh FDA put uh additional language in the labels uh to warn people about the this is actually 2014, not 15, 2014, actually, it actually 3-3-2015, uh about the safety of testosterone. And they told the 11 makers of testosterone products that they had to do a major outcome trial. Uh they then came to uh us, uh, and I was the study chair for this trial. It was very hard. We had to do it in the middle of the pandemic, and but we did financially get it done, and we got what I think is a useful answer, but with many questions remaining.

Sara Klockars 3:32

That is a great overview of the history. It's been going on for quite quite some time. Yes. Um so I think, you know, before we dig into some of the trial specifics, could we just get an overview of the trial? Um, kind of looking at the study population, the size, the duration. I know we had some questions on our um from our reviewers about, you know, is this observational data or cohort? So I think we're going to try to work something in that it's a randomized trial. But if you could just give us some background.

Steven E. Nissen 4:07

Right. Well, what we designed was a randomized controlled trial. Uh, like most modern trials, it was event-driven. The FDA wanted us to rule out an upper confidence interval of 1.5. Now, to do that, we needed about 256 morbid mortal events. And so it was designed to do that, and it ultimately required 5,200 odd patients to get enough events to qualify for answering the question of whether we could rule out an upper confidence interval of 1.5. Now, for those of you that are not familiar with non-inferiority trials, you need uh a point estimate of the hazard ratio of about 1.25 in order to rule out 1.5, 1.26 actually. So if we said seeing more than a 26% increase in cardiovascular events, we would not have found non-inferiority.

Sara Klockars 5:15

So in our article, when we say um we suggest that transdermal testosterone gel daily for about 22 months, and then we have the target testosterone levels in there, does not increase risk of cardiovascular death, heart attack, or stroke more than placebo.

Steven E. Nissen 5:32

Um is that how you I would be first of all, in public communications about this, I've been extremely cautious. This was a very carefully documented group of men that had what is known by endocrinophysis as hypogonadism. I prefer the term androgen deficiency. They had to have a testosterone level of less than 300 nanograms per deciliter on two occasions, drawn in the morning, and they were then given testosterone gel, which was titrated to achieve levels between 350 and 750, not above uh that level. If they went above that level, even on the lowest dose, they were discontinued for safety reasons. And for uh this population, we did not see an excess of cardiovascular events. This is not, however, the population that's being treated with testosterone in the United States. FDA data shows that 50% of men who go to low T centers, which are cropping up in every shopping mall, are getting testosterone without even having their levels checked. And I want to be as clear as I can be that this is not an endorsement for using testosterone widely in aging men who did not meet the criteria for this trial.

Sara Klockars 7:03

You bring up a great point in that this trial actually goes along with the guidelines. So the endocrinology society, the AUA guidelines, you must have symptoms and the fasting testosterone levels below 300 on two occasions. Um, and back to your comment earlier, Steve, about the FDA warning, they actually made all of the manufacturers put some wording into their package labeling. Yeah. So we have that as well, where they, you know, say that this is not for patients with age-related hypogonadism. So just to make that clear, yeah, I I appreciate that point.

Steven E. Nissen 7:41

And it's also not for bodybuilders and athletes. And I mean, I think we all know that this is a drug that can be abused, which is why it's a controlled drug.

Sara Klockars 7:51

Yep. Great. And we had some questions come up about our wording in our um article as well. And so I think we will put in there too fasting total testosterones, or folks were asking about free testosterone levels. Um, but I believe, I mean, the Traverse trial looked at the total serum testosterone levels.

Steven E. Nissen 8:14

We did, but we also, you know, we have data on the free testosterone levels. But you know, you can only design a trial around one parameter, and the most universally available is is the total uh testosterone levels. So that's what we did. Um, but it it all it all gives you essentially the same answer, no matter how you look at it.

Sara Klockars 8:38

Yes. Okay, so here's something else that I want people to know about the trial.

Steven E. Nissen 8:44

Whenever you do a trial in symptomatic patients, patient retention is difficult. And there was a very high rate of discontinuation of treatment and of people withdrawing consent for the trial. And the data are all in the manuscript, but I want to make sure everybody understands that if you're not taking a drug, you can't have a safety-related event. And so this was an intention to treat trial, which means that even people after they were off of study drug were continued to be followed for morbid mortal events, and that can bias a trial toward the null hypothesis, towards a hazard ratio of one. So we built in a principal sensitivity analysis that looked at people while on study drug and for a year thereafter, and we did post hoc analyses looking at people on study drug and for 30 days thereafter. And all of those analyses gave the same answer, very close to a neutral effect for testosterone. It does not mean, however, that there were not safety findings. There were other safety findings, some of which were unanticipated.

Sara Klockars 10:05

That's a great segue. Can we move on and discuss some of the adverse effects that you identified in the trial?

Steven E. Nissen 10:13

Yeah. So uh we did have a statistically significant excess of atrial fibrillation. Uh the event rates were modest. They were, you know, there were was 3.5% in the testosterone group and 2.4 percent in the placebo group. In the adjudicated endpoints table, that there was an excess of venous thromboembolic events and there was an excess of pulmonary embolism cases. So those are all you know things that people have to be aware of. And we we we do think that there are reasons to believe that uh testosterone can be pro-thrombotic, and we would urge caution in giving the drug to someone who's had a pulmonary embolism or any deep venous thrombosis. Now, the atrial fibrillation uh signal was not terribly strong, but if you look at uh all the non fatal arrhythmias in the trial, it was highly significant. Number needed to harm you got there is relatively low, it's 52. Uh the again, the acute kidney injury data just at the borderline of statistical significance. And for people that are savvy about trials, you know that you can see this sort of thing by chance when you look at you know dozens of safety endpoints, getting something with a p-value of 04 is not uncommon. Having said that, people need to be aware of this that we did not show that testosterone had no adverse effects. We showed that it did not increase the risk of major adverse cardiovascular events, but there were other safety events of concern.

Sara Klockars 12:02

Correct.

Steven E. Nissen 12:04

Oh, yeah, go ahead.

Sara Klockars 12:05

Go ahead.

Craig D. Williams 12:07

I just asked for a quick seat. You know, I know one thing is that got changed as this piece was evolving that this was transdermal, and reasons think that might be safer than other forms of testosterone people might be getting, especially if some of these kind of pop-up clinics is as Steve mentioned. But was there any ever any discussion of using any other doses form besides the transdermal or Steve? Or that was always a design from day one?

Steven E. Nissen 12:29

So that was designed from day one mainly because the maker of the uh the gel was uh the lead sponsor, and that was Av V, and they basically came up with a lot of the money. I will also tell you, I have reviewed the data for the injectables, and I agree with everything you said. There is a pretty strong signal on worsening hypertension with injectable forms of testosterone. I do not think we can consider these things to be entirely equivalent. I think what we showed was the relative cardiovascular safety of the topical uh gel, but I don't know about these other forms, and I do think that it's never going to be studied. So I think people just have to be aware that there are really significant risks.

Sara Klockars 13:21

So, do you think we can still say, plus, there are still uncertainties with other dosage forms and with longer-term use. So a lot of people will get started on testosterone and may not um get the labs done, or they may get the labs done, and this trial is only 22 months.

Steven E. Nissen 13:41

And so Sarah, your point is very well taken that we studied these people for a median of 22 months. There are men that are going to be on this therapy for five and even 10 years, and we did not, you know, we couldn't do a trial like that. It was would have been just logistically almost impossible. As it is, this was very difficult to get to get to get done. So I don't I do think that that long-term use has uh uncertainties without question. I would also want to point out to you that when we presented the data at the Endocrine Society, we presented data on five of the seven substudies, and one of them gave a very big surprise. Uh, and this will be published. Uh, but there was an excess of fractures in men that got testosterone. And the fracture subcommittee that took a look at this, and they adjudicated these fractures, were astonished because it has been believed for a long time that testosterone improves bone health rather than worsens bone health. That's not what we saw in the trial. And you know, stay tuned and we'll give you more details when that manuscript is published.

Sara Klockars 14:58

That's great. I was going to actually ask about some of the other things that the Traverse trial looked at, and that was one of them. So thanks for bringing that up.

Steven E. Nissen 15:06

Yeah, there was a couple of others just before we lose all of our time. Uh, there was a study on anemia, uh and that will also be published. And we reported at the Endocrine Society meeting that the that testosterone did correct anemia in anemic men more often than placebo, and it prevented development of anemia uh in in men during the course of the trial. So there was a favorable effect. We'll be reporting on the changes in sexual function and mood and depression. We did we collected as much data as we could about both the safety but also of the efficacy of testosterone in relieving the symptoms of concern.

Sara Klockars 15:51

That's great, and some much needed data to help guide some decisions. So uh I wanted to kind of get into the bottom line that we're gonna say in our article, and it's basically uh aligning with the guidelines, aligning what we talked about earlier with the trials, considering testosterone only for men with symptoms and low testosterone. Um and levels under 300 don't automatically need treatment unless you also have symptoms. And um, then we go on to say a little bit about where the evidence is, and you alluded to some of this, but right now, currently, um, you know, testosterone may provide a small improvement in libido or erectile function, but data, published data to date, um, there's no benefit for low energy cognitive impairment, fatigue, quality of life that we're aware of. So do you agree, you know, kind of with this bottom line for our readers?

Steven E. Nissen 16:54

Yeah, I do agree with it. Um, you know, they're, you know, again, I without giving away the subsequent, there's gonna be a whole series of manuscripts, many of them published in very top-tier journals that are gonna tell you more about everything that the drug does, including its effect on sexual function and libido. And we collected as much information as we could, knowing that this trial would only be done once, never going to be done again. So we did everything we could, and we also collected data on prostate health. A lot of concern about uh testosterone and prostate health. We did not see an excess of either high grade or low-grade prostate cancers in those men that were randomized to testosterone, but again, that was only for 22 months. You know, carcinogenic effects of drugs generally take many years to develop. So I'm not sure we've rule that out entirely.

Sara Klockars 17:55

Craig, do you want to comment on like when you decide or have a discussion with a patient about using testosterone, you know, how do you kind of have that conversation discussing the pros and cons?

Craig D. Williams 18:08

Yeah, honestly, outside of our specialists doing this for uh, you know, in some obviously special pediatric cases, and it's and it's say in adult cases where it's it's pretty clear, you know, there truly is a hypokinalism uh issue, it's in the otherwise, I don't know, healthy worried or how we might want to explain, like for the symptoms we have up here in the last slide, as far as low libido rectile dysfunction, patients who perceive there might be a cognitive benefit, uh we're just not initiating there, and I don't know if anywhere specialists are there either, at least in the academic setting. So, and and it's a little against the endocrine guidelines to just, you know, symptoms and the testosterone level below X. Uh, you know, it's it's just there's still a lot of questions there. So it seems like you know, benefits maybe to come from this, but it looks like the benefits aren't fantastic. This is a lot of times I tell my students, learners like an absence of something bad is not a reason to use a drug. It's you know, you need to see the good. And so I'll I'll be looking forward to the good that's coming. But yeah, the literature now doesn't support a lot of benefit, and people don't have a clear hypoganasm state, so we're just not doing this much in patience.

Steven E. Nissen 19:22

I think we need to be clear that men seek this treatment because they they anticipate the fountain of youth, they want to have the the sexual performance they had when they were 18 years old, and you know, they want to you know have stronger muscles and all of that, and the promise of this transforming people's lives is a false promise. And on the other hand, if you have similar coupling, uh, and you know, you have documented low levels on two occasions, it's not unreasonable to give this a try, assuming that you don't have high risk of thromboimism or atrial fibrillation. I think those things would make would give me pause, but it's also not unreasonable to but also explain to men that they should not expect a dramatic change in their physical functioning when they uh get on testosterone therapy.

Sara Klockars 20:24

Yep. And we did have some questions come up, and a couple of our reviewers brought up the intramuscular forms um being linked to more cardiovascular events. So I know in 2015 there was a retrospective cohort that kind of looked into this, and you know, the intramuscular injectable forms were linked to more events, and so we know we had some reviewers that said they would, you know, prefer to use the transdermal if they were going to use this in their patients. Um, I don't know if if Craig, you want to talk about that or yeah, I don't know.

Craig D. Williams 21:02

We can say a lot more than our earlier comments, just that uh there'd be reasons to think that uh other systemic form, you know, there's oral options as well. And the more you're putting these hormones through the liver, a lot of the coagulopathies probably come from effects in hepatocytes and the analogy of estrogen in women. We learned a lot a lot of lessons about uh hormone placement therapy in women 30 years ago and 20 years ago, and there's evidence there too that transdermal doesn't carry the risk, and that that's a great other topic for another time, but but there's analogous uh lessons learned from hormone placement therapy in women and reasons to believe that yeah, pharmacologically uh intramuscular and especially oral, but any non transdermal form um just not the same. Serum levels might be different, uh levels exposed in the cardiac tissue and liver tissue be different. So, as Steve says, this is a relative safety of a transdermal product, I think. Is the bottom line for the study. And so yeah, I would stick to transdermal if I'm trying to avoid adverse cardiovascular events at this point.

Steven E. Nissen 22:07

Yeah. I I I think uh Craig is absolutely right in what he says, but the other thing is that we should uh, you know, men should understand that they should seek treatment from a recognized expert in hypogonadism. You know, often that's an endocrinologist uh or a urologist, although it can certainly be a uh a generalist or a family practitioner, but it has to be somebody who's knowledgeable about this. And I don't want men going to these uh low T centers. You know, you can even get it, you know, over the internet. I just don't think that's a safe approach, and I think we've got to strongly discourage people from doing that.

Sara Klockars 22:50

Yeah, do you have any pearls or tips or you know conversations that have worked well for you? We actually had a question come in. How do you talk about this with patients in light of the low T supplement TV ads?

Steven E. Nissen 23:02

Yeah, well, I get the question from my cardiovascular patients, and they say, gee, you know, they want to get on testosterone therapy, and they often went to one of these shopping mall places, and you know, often they will tell me they never had their testosterone level checked. And when I when I actually check it, they're completely within the normal range. And so, you know, I think having a conversation, that's why, you know, it's why we publish these things, is so the medical community, you know, and frankly, you know, from a pharmacy community, I think pharmacists are a great source of information here. And I want to make sure that everybody understands the nuances here, that while we did show non-inferiority, this is by no means an endorsement for the inappropriate and widespread use of testosterone as a fountain of youth for aging men. Thank you, Sarah.

Craig D. Williams 23:58

Let's add to that, those are great comments. That if someone does have low testosterone levels and they have and they have symptoms, they may not feel better. So don't be afraid to make sure you're circling back, and six, twelve months later, things don't feel better. Uh, it's not, it's not gonna kick in at year five, year six. And she said, this is safety data for a little under two years. Um, so don't be afraid to stop therapies if patients are dealing with it.

Steven E. Nissen 24:26

The favorable effects often emerge within three months. I mean, yeah. Yeah, you don't even need a year uh to to to do that. And um, and by the way, keep in mind you got to follow hematocrit. I mean, we we stopped the drug if they on the lowest dose of the hematic went above 54%, and some of them did. So those are all things that they have to be thought about. And I think this concept of stopping it if symptoms don't improve in six to twelve months is very, very good advice. Yeah.

Craig D. Williams 24:58

Yeah, that's advice for lots of drugs. I'm not a huge fan of. Get a petenoids too, but try it, but you know, ask them and stop it soon if it's not working. So yeah. Yeah.

Sara Klockars 25:07

We did have um oh, so sorry, go ahead, Doug.

Douglas S. Paauw 25:11

Yeah, Steve, I I thought that what you mentioned about the bone was really intriguing because that's been for me, that's been the one thing that I felt, you know, identifying some of these folks might be an issue. Some of them have a little lower bone mass because of their hypogonadism, and and I think that's really helpful information because I agree totally with the points made about the limited benefits. Uh, I think for me, for my patients who have been looking for it, the one thing I've seen some benefit for has been potentially libido, but the other things I totally haven't seen any benefit. And and uh yeah, the bone density thing was the was the one thing in fractures that I felt sort of that I needed to be more aggressive to look for. And anyway, I find that intriguing.

Steven E. Nissen 26:00

You'll want to look carefully when we publish it at the effects of on libido in the testosterone group and in the placebo group. One of the most effective ways to increase libido that I know of is placebo. And uh you may remember that that's what happened in a study of using testosterone to increase libido in women, is the placebo group did almost as well as the treated group. So, you know, it'll be interesting. We all want to take a look at the placebo control data, which I think will be more illuminating.

Sara Klockars 26:37

That's great. And so before we move on, we did have many questions coming in about monitoring. So if we could just go back to that topic real quick. Um, in our article, we have, you know, to monitor testosterone hematocrit in three to six months. And I believe then the guidelines recommend every six to 12 months thereafter. Um different guidelines say different things, but I just didn't know um how often did you check in the study or how often would you check in practice?

Steven E. Nissen 27:09

Well, let's talk about practice first of all, because that's what really people want to know about. You know, I would start it, I would check levels in three months, and as you suggested here, um PSA is going to go up, by the way. It does go up, we know that. Um, but you know, it's not at least not producing an acute uh carcinogenic effect. Um, I think you check testosterone levels, you check chematocrit. If levels are still low, you titrate to the next highest dose level, and you do that until you get into a therapeutic range. And once you're there, you can probably uh not measure it as often, maybe every six months thereafter.

Sara Klockars 28:05

Sounds sounds like a good recommendation, and that's what I've seen in the guidelines. So that's helpful. We might actually add that in. Um we also had some feedback about the PSA kind of being controversial, and you wouldn't necessarily need to check that. So we might edit this wording. Um and then definitely keep the stop if symptoms don't improve. Awesome.

Steven E. Nissen 28:28

Yeah.

Sara Klockars 28:29

I want to share a clinical resource with you. We have um a nice chart on the comparison of testosterone products. Uh, has dosing and monitoring, and it reviews the pros and cons of each formulation. There's even some tips for application and also, you know, best timing to draw uh or to check um testosterone levels since each formulation you know peaks at a different time, that sort of thing. So um check out this great chart.

Narrator 28:58

We hope you enjoyed and gained practical insights from listening into this discussion. Now that you've listened, pharmacists, physicians, and nurses can receive CE credit. Just log into your pharmacist letter or prescriber's letter account and look for the title of this podcast in the list of available CE courses. You'll also be able to access and print out additional materials on this topic, like charts and other quick reference tools from the pharmacist letter and prescribers letter websites. If you're not yet a pharmacist letter or prescribers letter subscriber, find out more about our product offerings at TRCHealthcare.com. Be sure to follow or subscribe, rate, and review this show in your favorite podcast app. It helps spread the word about our show and is a great way for you to let us know how we're doing. You can also reach out to provide feedback or make suggestions by emailing us at contact us at trchealthcare.com. Thanks for listening to Medication Talk.